OR09

Gene therapy for familial hemophagocytic lymphohistiocytosis related to Munc 13-4 deficiency

J S Diana(1,2) C Lagresle-Peyrou(1,3) E Magrin(1,2) N Sorel(1,3) C Aussel(2) U Chartral(2) E Schwartz(1,2) A Gabrion(2) C Roudaut(2) A Maullet(2) Y Aslan(1,3) E Mathe(1,2) F Lefrere(4) A Galy(5) D Moshous(4) M Cavazzana(1,2,3)

1:Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France; 2:Department of Biotherapy, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, 75015 France; 3:UMR 1163, INSERM, Paris Descartes University Sorbonne Paris Cité, Imagine Institute, Paris75015, France; 4:Department of Pediatric Immunology, Hematology, and Rheumatology, Necker-Enfants Malades University Hospital, APHP, F-75015 Paris, France; 5:US35 INSERM, ART-TG ; Corbeil-Essonnes, France

Familial Hemophagocytic Lymphohistiocytosis type 3 (FHL3) is a rare genetic disorder, accounting for 30% of all forms of FHL. This condition is characterized by a defect in the cytotoxicity of T and NK cells, leading to hyperinflammation and the infiltration of activated cells in organs. FHL3 is caused by mutations in the UNC13D gene, which encodes the Munc 13-4 protein. Currently, hematopoietic stem and progenitor cell (HSPC) transplantation is the only curative treatment available. However, complications such as graft-versus-host disease or graft rejection are common when using partially HLA-compatible donors. Therefore, gene therapy may present a promising therapeutic option. We have applied this approach to human cells by utilizing a third-generation self-inactivating lentiviral vector. This vector expresses a codon-optimized UNC13D gene under the control of the EF1 alpha promoter. We successfully transduced HSPCs and CD3+ T-cells, and restored the cytotoxic functions. The average vector copy number achieved was 1.3 ± 0.7, making it suitable for a clinical application. Both in vitro and in vivo biodistribution studies showed no signs of toxic effects. Overall, our results demonstrate, for the first time, the effectiveness of UNC13D gene transfer into HSPCs and T-cells derived from patients with Munc 13-4 deficiency. A phase I/II clinical trial targeting Munc 13-4 deficiency has recently received approval from regulatory authorities, and we expect to begin recruiting the first patients in the coming months